In spite of the recent surge in genetic engineering research, there is still a widespread use of traditional chemical methods of peptide synthesis. Although genetic methods may be far more efficient for the production of certain large peptides such as insulin or growth hormone, chemical synthesis is still more valuable in the manufacture of smaller peptides (less than 50 amino acids) and their analogues, which may contain D-amino acids or other substituents which do not occur naturally.
One popular method of chemical synthesis is the Merrifield method of solid phase peptide synthesis (J. Am. Chem. Soc., 85:2149, 1963; Biochemistry, 3:1385, 1965) which involves the reaction of a protected amino acid in the presence of triethylamine with a polymeric support or substrate. U.S. Pat. No. 3,925,267 teaches a styrene-derived polymer useful as a substrate in the controlled synthesis of polypeptides. Specifically, this invention requires the chloromethylation of the aromatic rings to activate the polymer used as a carrier. U.S. Pat. Nos. 4,079,021 and 4,133,942 are also directed to styrene-derived polymers which must be chloromethylated in order to react with the first amino acid. U.S. Pat. No. 3,948,821 also describes a chloromethylation procedure for polymer activation, in which the major modification is the addition of non-reactive polar solvents to eliminate the competing reaction between the chloromethylated resin and the solvent ethanol, which slows down the initial rate of esterification. It is also known to modify polystyrene to produce various polymeric reagents (Pepper, et al., J. Chem. Soc., 4097, 1953); displacement of the chlorine atom by a nucleophile may give rise to a variety of different reagents. Carboxylic acids have been linked to chloromethylated polystyrene through an ester bond to produce peptides (Merrifield, et al., J. Am. Chem. Soc., 85, 2149). The disadvantage associated with this type of reaction, however, is that the weak carbon-oxygen bond of the ester linkage requires avoiding the use of strong bases and nucleophiles.
Many of the inherent disadvantages involved in the solid phase method of synthesis, such as difficulty in isolation of the peptide and possible contaminating side reactions, are avoided by the use of polymeric reagents rather than polymeric supports. Israeli Patent Application No. 59689 discloses a polymeric reagent prepared by Friedel Crafts acylation of polystyrene with substituted benzoic acids. The present invention relates to a polymeric reagent prepared by the sulfonylation of polystyrene by the addition of a substituted benzene sulfonyl group to the phenyl group of the polymer backbone. The polymeric reagent so produced shows a surprising reactivity and is particularly useful in the process of peptide synthesis.